The compound N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide of formula (1A) and derivatives thereof have been disclosed in WO 2011/051540. Compound of formula (1A) and its derivatives are potent androgen receptor (AR) antagonists that are useful in the treatment of cancer, particularly prostate cancer and other diseases where AR antagonism is desired.

WO 2011/051540 discloses a process for the preparation of the compound of formula (1A) through 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile intermediate of formula (V). The intermediate of formula (V) was prepared as shown in Scheme I:

This process comprises reacting 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (I) with 4-bromo-2-chlorobenzonitrile (II) in a Suzuki reaction to obtain 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-benzonitrile of formula (III). The Suzuki reaction is carried out in the presence of bis(triphenylphosphine)palladium(II) chloride catalyst and sodium carbonate base in THF-water solvent. After the reaction has completed the solvents are distilled to almost dryness and water is added to precipitate the compound of formula (III). The isolated compound of formula (III) is subsequently treated with 10% HCl in ethanol to obtain 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile hydrochloride salt of formula (IV) which is isolated. Finally, 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile of formula (V) is obtained by treating the compound for formula (IV) with sodium hydroxide in water-methanol solvent.
A similar process for preparing the compound of formula (V) is disclosed in WO 2012/143599. The Suzuki reaction is carried out in THF-toluene-water solvent and also a phase transfer catalyst (TBAB) is used. The isolation of the compound of formula (III) is carried out by adding water and distilling the isolated organic phase close to dryness followed by adding ethanol and filtering the crystalline product. The isolated compound of formula (III) is treated with 10% HCl in ethanol to obtain the compound of formula (IV). This compound is dissolved in methanol for treatment with activated carbon and celite. Part of methanol is distilled off and water and 50% NaOH is added. After the reaction is complete methanol is distilled off and water is added for precipitation of the compound of formula (V). The total yield of all three stages is 84.5%.
The above mentioned processes have several drawbacks. The amount of the expensive bis(triphenylphosphine)palladium(II) chloride catalyst needed to carry out the Suzuki reaction effectively is high, around 5 mol-%. The use of ethanolic HCl is impractical and the work-up of the process is very complex due to many distillations to dryness which is a difficult operation to handle in a large scale. Moreover, several isolations make the process cumbersome and lower the yield.
Thus, there is a need for a more practical and economical process that is suitable for the manufacture of intermediates such as the compound of formula (V) in a large scale.